BINDING OF VIRAL-ANTIGENS TO MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-IH-2D(B) MOLECULES IS CONTROLLED BY DOMINANT-NEGATIVE ELEMENTS AT PEPTIDE NON-ANCHOR RESIDUES - IMPLICATIONS FOR PEPTIDE SELECTION AND PRESENTATION
D. Hudrisier et al., BINDING OF VIRAL-ANTIGENS TO MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-IH-2D(B) MOLECULES IS CONTROLLED BY DOMINANT-NEGATIVE ELEMENTS AT PEPTIDE NON-ANCHOR RESIDUES - IMPLICATIONS FOR PEPTIDE SELECTION AND PRESENTATION, The Journal of biological chemistry, 271(30), 1996, pp. 17829-17836
Binding of viral antigens to major histocompatibility complex (MHC) cl
ass I molecules is a critical step in the activation process of CD8(+)
cytotoxic T lymphocytes, In this study, we investigated the impact of
structural factors at non-anchor residues in peptide-MHC interaction
using the model of lymphocytic choriomeningitis virus (LCMV) infection
of its natural host, the mouse, Altering viral genes by making reasso
rtants, recombinants, and using synthetic peptides, CD8(+) cytotoxic T
lymphocytes were shown to recognize only three H-2D(b)-restricted epi
topes, GP amino acids 33-41/43, GP 276-286, and NP 396-404, However, L
CMV NP and GP proteins contain 31 other peptides bearing the H-2D(b) m
otif, These 34 LCMV peptides and 11 other known H2-D-b-restricted pept
ides were synthesized and examined for MHC binding properties, Despite
the presence of the H-2D(b) binding motif, the majority of LCMV pepti
des showed weak or no affinity for H-2D(b), We observed that dominant
negative structural elements located at non-anchor positions played a
crucial role in peptide-MHC interaction, By comparative sequence analy
sis of strong versus non-binders and using molecular modeling, we deli
neated these negative elements and evaluated their impact on peptide-M
HC interaction, Our findings were validated by showing that a single m
utation of a favorable non-anchor residue in the sequence of known vir
al epitopes for a negative element resulted in dramatic reduction of a
ntigen presentation properties, while conversely, substitution of one
negative for a positive element in the sequence of a non-binder confer
red to the peptide an ability to now bind to MHC molecules.